Alcoholism and alcohol dependence are important contributors to health problems facing US veterans. Alcoholism is a multigenic and polygenic disease: that is, many genes contribute modest effects to enhance risk or protection. Together, genetic factors appear to contribute approximately half of an individual's total risk, with the other half coming from environmental factors, such as socioeconomic, family, and peer attributes. We can now only predict that an individual may be at an increased statistical risk based on his or her genetic relationships to alcoholics. One important goal is to be able to predict actual individual differences in risk, based on knowledge about specific genes. There is currently no animal model that captures the full range of alcohol withdrawal symptoms. During 29 years of continuous funding, this Merit Review Program has established and studied a number of genetic animal models for aspects of alcohol (ethanol) dependence, and has contributed to the identification of the first gene influencing a drug-dependence related behavioral trait, Mpdz, influencing ethanol withdrawal seizures. Because of the high degree of mouse/human genetic homology (approx. 85%), genes mapped in mice are able to predict human gene locations. However, to date, nearly all gene mapping efforts for ethanol dependence by any group have focused on either withdrawal seizures or alcohol preference drinking. Beginning in 1999, we began studies in several behavioral domains to start mapping the landscape of withdrawal more broadly. An important goal is to identify the genes responsible for increased risk for and protection against the several different symptoms of alcohol dependence. In filling this gap, this project will (1) develop more comprehensive assessment assays to describe ethanol withdrawal effects across multiple behaviors, including anxiety, activity, motor performance, and withdrawal-induced drinking; (2) elucidate the time course of each of these withdrawal effects; (3) identify genes which demonstrate withdrawal-induced changes in expression; and (4) continue to support the most widely used genetic animal model for ethanol dependence syndromes, the Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant mouse lines. These studies, through identification of gene targets that are affected by alcohol dependence and withdrawal symptoms, will ultimately directly suggest possible pharmacotherapies for the problems underlying alcoholism. PUBLIC HEALTH RELEVANCE: The VA's leadership in substance abuse, a VA Research Priority Area, and in particular alcohol research is well known. Alcohol-related disorders have consistently been diagnosed in a large proportion of VA hospital patients. In a study of all male veterans (n=539,557) treated at VA medical centers during a one-year period, nearly one-quarter had a substance-related diagnosis, and of those, 87.7% were diagnosed with Alcohol Dependence. Female and male veterans also have much higher prevalence rates than the general population [*] for Alcohol Dependence. Substance abuse including alcohol use disorders is among the top 3 diagnoses in the VA healthcare system [VA Research Currents, January, 2007]. The May, 2008 VHA Substance Use Disorder (SUD) Factsheet reported that 355,000 veterans who presented at VA health facilities had SUD other than nicotine dependence. [*] Davis TM, Bush KR, Kivlahan DR, Dobie DJ, Bradley KA. (2003). Screening for substance abuse and psychiatric disorders among women patients in a VA Health Care System. Psychiatr Serv 54:214-8.